Process for producing N-(D-α-methyl-β-mercaptopropionyl)-L-proline and its intermediate

ABSTRACT

A highly convenient and efficient process for economically producing in a high yield high-quality captopril which is remarkably reduced in the content of impurities and has a high melting point and intermediates for synthesizing the same which contain only a small amount of precursors as impurities and have excellent qualities. The process comprises subjecting an acid halide and an L-proline to the Schotten-Baumann reaction and eliminating the impurities formed as the by-products in the form of the precursors represented by general formula (5) or (6) by treating, during or after the Schotten-Baumann reaction, the aqueous medium solution with active carbon or crystallization followed by deacylation. In the formula, R 1  represents acyl and n represents an integer of from 2 to 4. ##STR1##

This is a PCT/JP96/02902 Oct. 7, 1996 now WO 97/12858 Apr. 10, 1997.

FIELD OF THE INVENTION

The present invention relates to a process for producingN-(D-α-methyl-β-mercaptopropionyl)-L-proline of the formula (4) ##STR2##and its synthetic intermediateN-(D-α-methyl-β-acylthiopropionyl)-L-proline of the formula (3) ##STR3##or N-(DL-α-methyl-β-acylthiopropionyl)-L-proline.

BACKGROUND TECHNOLOGY

N-(D-α-methyl-β-mercaptopropionyl)-L-proline (4) has potent angiotensinconverting enzyme inhibiting activity and is an antihypertensive agentgenerically called captopril (erg. Biochemistry, 16, 5487 (1977)).

Various methods are known for the production ofN-(D-α-methyl-β-mercaptopropionyl)-L-proline (4) (hereinafter alsocalled captopril). For instance, in Japanese Kokoku PublicationSho-60-56705, Japanese Kokai Publication Hei-5-17435 and Japanese KokaiPublication Hei-5-221966 and elsewhere, there are disclosed processesfor producing captopril which comprises deriving anN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) from aD-α-methyl-β-acylthiopropionic acid halide orDL-α-methyl-β-acylthiopropionic acid halide and L-proline by utilizingthe Schotten-Baumann reaction and then subjecting the intermediate (3)to deacylation.

While the medical and medicinal expenses are on a growing trend,captopril is expectedly one of large-sale generic drugs and it is ofgreat significance to develop a process for producing high-puritycaptopril at low cost and in easy and simple manner.

As for the specifications of captopril, the Japanese PharmaceuticalIndex requires that the captopril bulk substance contains not less than97.5% of captopril and has a melting point of 105° C. to 110° C. andthat the content of captopril disulfide, which is one of relatedsubstances (organic impurities), is not more than 2.5%, among others.The U.S. Pharmacopeia requires, among others, that the content ofβ-mercapto-α-methylpropionic acid as a related substance (organicimpurity) is not more than 0.1%. In view of the nature of a medicineingredient, it is needless to say that said bulk substance can hardlycontain other related substances or organic impurities not referred toin such specifications or, in other words, it is strongly desired thattheir contents do not exceed 0.1%.

Concerning the quality of captopril products obtained by subjecting theabove-mentioned acid halide and L-proline to Schotten-Baumann reaction,followed by deacylation, the impurities possibly contained therein andthe methods of preventing the formation thereof, literature referencesdisclose, for example, as follows:

In the above-cited Japanese Kokai Publication Hei-5-221966, it isdescribed that N-α-methyl-β-methyl-β-hydroxycarbonyl)ethylthiopropionyl!-L-proline of theformula (7) given below, or N-acetyl-L-proline, among others, is formedas a by-product in the Schotten-Baumann reaction. ##STR4##

According to the teaching disclosed in said Japanese Kokai PublicationHei-5-221966, however, the Schotten-Baumann reaction and the subsequentdeacylation are carried out in a continuous manner, so that it is notvery certain in which step the above-mentioned by-products are formed asimpurities. For preventing the formation of these products according tosaid teaching, the pH, temperature and D-α-methyl-β-acylthiopropionicacid halide/L-proline mole ratio, among others, are important incarrying out the Schotten-Baumann reaction. As optimal values, there arementioned an initial pH of 9.9 to 10.1, a final pH of 10.9 to 11.0, areaction temperature of not higher than 10° C., and aD-α-methyl-β-acylthiopropionic acid halide/L-proline mole ratio of 1.0to 1.1.

In U.S. Pat. No. 5,387,697, it is disclosed that the compound of theformula (8) ##STR5## is formed as a by-product during theSchotten-Baumann reaction and it is described that for preventing theformation of this impurity, the Schotten-Baumann reaction should becarried out at 0° C. to 5° C. in 0.25 M potassium phosphate buffersolution, while adjusting the pH to 7.5 to 8.5 with potassium hydroxide.However, in said patent specification, no mention is made of N-α-methyl-β-(β-methyl-β-hydroxycarbonyl)-ethylthiopropionyl!-L-proline(7) and no reference is made to the relation between the compound (7)and the compound of the above formula (8).

As regards the reaction conditions to be employed for preventing theformation of the compound of formula (8), which is a precursor of thecompound of formula (7), in the Schotten-Baumann reaction, thosedescribed in U.S. Pat. No. 5,387,697 Specification constitute the onlyprior art, which, however, has the following problems: for instance, theuse of the phosphate produces a problem in waste water treatment becauseof its eutrophication potential, the pH adjustment by adding potassiumhydroxide during reaction makes the procedure complicated, and theformation of the compound of formula (8) can be prevented only to anunsatisfactory extent.

Japanese Kokai Publication Hei-7-10835 discloses a process for purifyingcaptopril which comprises treating an acyl-protected captoprilintermediate of the formula (3) given above with active carbon andradiolite in an organic solvent to thereby eliminate the disulfiderepresented by the formula (9) given below, which otherwise possiblygets into the product captopril. ##STR6##

However, there is no mention whatever of the efficiency of theelimination of by-products of the formula (5) shown below and theby-product of the formula (6) shown below. In the formulas, n representsan integer of 2 to 4 and R₁ represents an acyl group. ##STR7##

Check experiments performed by the present inventors showed that theabove-mentioned treatment with active carbon etc. in organic solventscan hardly be expected to be effective in eliminating the by-productsrepresented by the above general formula (5) or formula (6).

U.S. Pat. No. 5,387,697, CN Patent Publication 1,051,909 and CN PatentPublication 1,034,920, for instance, respectively describe thecrystallization of the acyl-protected captopril intermediate of theabove formula (3) from an aqueous solution thereof. In each case, thecrystallization is effected at room temperature or a temperaturetherebelow and there is no mention whatever of the efficiency of theelimination of the by-products represented by the above general formula(5) or formula (6). Check experiments made by the present inventors,however, revealed that these methods can hardly be expected to beeffective in removing the by-products represented by the above generalformula (5) and the by-product represented by formula (6).

Thus, so far, neither a process for producing captopril or its acylatedintermediate by which the by-product formation can be prevented nor amethod of purification by which by-products can be removed fromcaptopril or its acyl-protected intermediate contaminated therewith hasbeen available.

As detailedly described hereinabove, the prior art captopril productsobtained by the Schotten-Baumann reaction between the above-mentionedacid halide and L-proline and the subsequent deacylation arecontaminated with various impurities and it is very difficult to obtainhigh-quality captopril.

SUMMARY OF THE INVENTION

In view of the foregoing, it is an object of the present invention toprovide a very easy and simple and efficient process for economicallyproducing in high yields high-qualityN-(D-α-methyl-β-mercaptopropionyl)-L-proline (4) (captopril) containingvery small amounts of various impurities, in particular N-α-methyl-β-(β-methyl-β-hydroxycarbonyl)ethylthiopropionyl!-L-proline(7), which is difficult to eliminate, and having a high melting point.

Another object of the present invention is to provide a very easy andsimple and efficient process for producing, in high yields and at lowcost, an N-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) orN-(DL-α-methyl-β-acylthiopropionyl)-L-proline of good quality, whichserves as an intermediate in the synthesis ofN-(D-α-methyl-β-mercaptopropionyl)-L-proline (4) (captopril) andcontains only small amounts of the compounds of the general formula (5)shown above and the compound of formula (6), which are precursors of N-α-methyl-β-(β-methyl-β-hydroxycarbonyl)-ethylthiopropionyl!-L-proline(7).

As a result of intensive investigations made by the present inventorsconcerning the each reaction method of carrying out the above-mentionedSchotten-Baumann reaction and deacylation reaction, and the purifyingmethod in an attempt to solve the above problems, the present inventorsarrived at a conclusion that for obtaining high-qualityN-(D-α-methyl-β-mercaptopropionyl)-L-proline (4) (captopril) in highyield, it is very important to prevent the formation of or remove, inparticular, the compounds of the above general formula (5) and thecompound of the above formula (6), which are precursors of N-α-methyl-β-(β-methyl-β-hydroxycarbonyl)-ethylthiopropionyl!-L-proline(7), and prevent, in the deacylation reaction step, the formation of N-α-methyl-β-(β-methyl-β-hydroxycarbonyl)ethylthiopropionyl!-L-proline (7)as a by-product.

The present inventors further found that N-α-methyl-β-(β-methyl-β-hydroxycarbonyl)ethylthiopropionyl!-L-proline (7)is formed under strongly alkaline conditions in the series of the stepsfor captopril formation, especially in the Schotten-Baumann reactionbut, under comparatively mild alkaline conditions, it remains in thestage of a precursor or precursors as represented by the above generalformula (5) or formula (6).

Based on the above findings, the present inventors concluded that it ispossible to reduce the content of the compound of the above formula (7)as an impurity in captopril products when, in the process comprising theSchotten-Baumann reaction and the deacylation reaction, the followingtreatments are carried out, either alone or in combination, underrespective specific conditions:

1 treatment for reducing the formation of compounds of the above generalformula (5) and the compound of formula (6),

2 treatment for preventing the conversion of these compounds to thecompound of the above formula (7), and

3 treatment for removing the compounds of the above general formula (5)and the compound of formula (6) by purification treatment with activecarbon, crystallization or the like. In the end, they have been led tocompletion of the present invention.

Thus, the gist of the present invention consists in that, in the processfor producing N-(D-α-methyl-β-mercaptopropionyl)-L-proline of theformula (4) ##STR8## by subjecting a D-α-methyl-β-acylthiopropionic acidhalide of the general formula (1) ##STR9## (wherein R₁ represents anacyl group and X represents a halogen) and L-proline of the formula (2)##STR10## to Schotten-Baumann reaction in a basic aqueous medium in thepresence of a deacidifying condensing agent to give the correspondingN-(D-α-methyl-β-acylthiopropionyl)-L-proline of the general formula (3)##STR11## (wherein R₁ is as defined above), followed by deacylation, thedeacylation of the N-(D-α-methyl-β-acylthiopropionyl)-L-proline iscarried out after removal of those impurities concurrently formed withthe above-mentioned objective substanceN-(D-α-Methyl-β-mercaptopropionyl)-L-proline, in their precursor stage,from the aqueous medium solution after commencement but beforecompletion of said Schotten-Baumann reaction or after completion thereofby treating said aqueous medium solution with active carbon at a pH nothigher than 12, to give high purityN-(D-α-methyl-β-mercaptopropionyl)-L-proline (4).

In another aspect, the gist of the present invention consists in that,in the production process mentioned above, theN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) formed is collected bycausing the same to perform crystallization at 35° C. to 100° C. underacidic conditions from the aqueous medium solution after completion ofthe Schotten-Baumann reaction, thus removing those impuritiesconcurrently formed with the above-mentioned objective substanceN-(D-α-methyl-β-mercaptopropionyl)-L-proline, in their precursor stage,and the thus-collected N-(D-α-methyl-β-acylthiopropionyl)-L-proline (3),either as such or after storage, is subjected to deacylation to therebyobtain high purity N-(D-α-methyl-β-mercaptopropionyl)-L-proline (4).

In a further aspect, the gist of the present invention consists in that,in the production process mentioned above, potassium hydrogencarbonateis caused to coexist as the deacidifying condensing agent in the step ofsubjecting the D-α-methyl-β-acylthiopropionic acid halide (1) andL-proline (2) to Schotten-Baumann reaction to thereby prevent theformation of the impurities which are otherwise formed in addition tothe above-mentioned objective substanceN-(D-α-methyl-β-mercaptopropionyl)-L-proline, in the stage of precursorsthereof, to prepare the correspondingN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) with a decreasedcontent of the precursors, which is then subjected to deacylation togive high purity N-(D-α-methyl-β-mercaptopropionyl)-L-proline (4).

DETAILED DESCRIPTION OF THE INVENTION

In the following, the present invention is described in detail.

According to the present invention, a D-α-methyl-β-acylthiopropionicacid halide (1) and L-proline (2) are subjected to Schotten-Baumannreaction. In the practice of the present invention, it is also possibleto use the above-mentioned D-α-methyl-β-acylthiopropionic acid halide(1) in the form of DL-α-methyl-β-acylthiopropionic acid halide andsubject the same to Schotten-Baumann reaction to give theN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) in the form ofN-(DL-α-methyl-β-acylthiopropionyl)-L-proline. In the Schotten-Baumannreaction mentioned above, various side reactions are presumable asfollows.

First, when exposed to water, the above-mentionedD-α-methyl-β-acylthiopropionic acid halide (1) is hydrolized to give thecorresponding carboxylic acid. When this by-product carboxylic acid isformed in large quantities, the above-mentionedD-α-methyl-β-acylthiopropionic acid halide (1) becomes short andL-proline (2) partially remains unreacted. When the amount of residualL-proline (2) increases, the L-proline (2) reacts with theabove-mentioned acid halide (1), theN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) orN-(DL-α-methyl-β-acylthiopropionyl)-L-proline to give, as by-products,the corresponding N-acyl-L-proline,N-(D-α-methyl-β-mercaptopropionyl)-L-proline (4) orN-(DL-α-methyl-β-mercaptopropionyl)-L-proline, etc.

In this way, side reactions based on the acyl group elimination ormigration are apt to occur in the reaction system and, furthermore,compounds of the above general formula (5) or the compound representedby formula (6) are readily formed as by-products in said system. Theby-products represented by the above general formula (5) or formula (6)are converted, under alkaline deacylation reaction conditions, to N-α-methyl-β-(β-Methyl-β-hydroxycarbonyl)ethylthiopropionyl!-L-proline,which is very difficult to remove.

It has not yet been reported that the above-mentioned compounds (5) andcompound (6) are precursors of the compound of the above formula (7) butis a novel finding obtained by the present inventors.

Among the compounds represented by the above general formula (5) whichare formed as products in the Schotten-Baumann reaction employed in theprocess of the present invention, the proportion of that compound of n=2is high and the formation of this by-product has a great influence onthe formation, as a by-product, of N-α-methyl-β-(β-methyl-β-hydroxycarbonyl)ethylthiopropionyl!-L-proline(7).

In accordance with the present invention, for obtaining captopril with avery low content of impurities such as N-α-methyl-β-(β-methyl-β-hydroxycabonyl)ethylthiopropionyl!-L-proline (7),the aqueous medium solution after commencement but before completion ofthe Schotten-Baumann reaction or after completion of said reaction istreated with active carbon, or theN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) in the form of crystalsor an oily substance, for instance, is treated with active carbon in anaqueous medium, to thereby remove the impurities formed as by-productsconcurrently with the above-mentioned objective substanceN-(D-α-methyl-β-mercaptopropionyl)-L-proline (4) in their precursorstage and, thereafter, the deacylation is carried out.

As the above-mentioned impurities, which are formed as by-productstogether with the objective substance, there may be mentioned, forinstance, the above-mentioned N-α-methyl-β-(β-methyl-β-hydroxycarbonyl)ethylthiopropionyl!-L-proline (7)etc. As the above-mentioned precursors, there may be mentioned theabove-mentioned compounds represented by the general formula (5) and thecompound of formula (6).

The conditions for the above-mentioned active-carbon treatment arepreferably such that the precursors mentioned above are not converted toN- α-methyl-β-(β-methyl-β-hydroxycarbonyl)ethylthiopropionyl!-L-proline(7) etc., and the N-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) orN-(DL-α-methyl-β-acylthiopropionyl)-L-proline does not undergodeacylation to give N-(D-α-methyl-β-mercaptopropionyl)-L-proline (4) orN-(DL-α-methyl-β-mercapto-propionyl)-L-proline or is not converted tothe disulfide. From this viewpoint, the pH to be employed in the abovetreatment step is generally not higher than 12 although it depends onthe treatment temperature and treatment period. At a pH exceeding 12,the above-mentioned conversion of the precursors may unfavorably occur.The preferred range of pH is 1 to 11, more preferably pH 2 to 10, andmost preferably pH 3 to 9. Within the above-mentioned range, a pH aroundneutrality is suitably selected, since theN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) andN-(DL-α-methyl-β-acylthiopropionyl)-L-proline, for instance, show lowsolubility under acidic conditions.

In the above-mentioned active-carbon treatment, the concentration of theN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) orN-(DL-α-methyl-β-acylthiopropionyl)-L-proline is not limited to anyparticular level but is preferably one at which theN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) orN-(DL-α-methyl-β-acylthiopropionyl)-L-proline is completely dissolved.Said concentration can be selected taking into consideration of theabove as well as the operability of each individual treatment procedureemployed and so forth.

The acid to be used for pH adjustment in the above active-carbontreatment is not limited to any particular species but includes, amongothers, mineral acids such as hydrochloric acid and sulfuric acid. Thebase to be used for pH adjustment is not limited to any particularspecies, either. Thus, said base may be such an inorganic base as sodiumhydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate,potassium carbonate, lithium carbonate, sodium hydrogencarbonate,potassium hydrogencarbonate or lithium hydrogencarbonate, or, whereappropriate, it may be an organic base such as an amine, which can forma salt with the carboxyl group of theN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) orN-(DL-α-methyl-β-acylthiopropionyl)-L-proline to thereby increase thesolubility thereof. These acids or bases may be used either singly or incombination as a mixture of two or more. Among them, preferred acids arehydrochloric acid and sulfuric acid, and preferred bases are sodiumhydroxide, potassium hydroxide and lithium hydroxide.

In the above-mentioned active-carbon treatment, the treatmenttemperature can be adequately selected within the range from freezingtemperature to boiling point depending on the pH, treatment time andother factors. Generally, a temperature around room temperature or belowis preferred.

In the above-mentioned active-carbon treatment, the amount of activecarbon to be used can be adequately selected taking into considerationof the active carbon species employed, the elimination effect thereof,the contents of the above-mentioned precursor substances, and so on.

In the above-mentioned active-carbon treatment, the time requiredtherefor can be known by high-performance liquid chromatographymonitoring, When powder-form active carbon is used, it is generallyabout 1 hour. In this case, granular active carbon can be used and it isconvenient to employ a method comprising passing the above-mentionedaqueous medium solution containing theN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) through a column packedwith granular active carbon, for instance.

In the practice of the present invention, it is also possible, in theabove-mentioned active-carbon treatment, to use an active carbon specieshaving low oxidizing activity or combinedly use a reducing agent so thatthe conversion of N-(D-α-methyl-β-mercaptopropionyl)-L-proline (3) orN-(DL-α-methyl-β-mercaptopropionyl)-L-proline, which results fromdeacylation, to the corresponding disulfide can be prevented.

In the practice of the present invention, the above-mentionedactive-carbon treatment is applied to the aqueous medium solution aftercommencement but before completion of the Schotten-Baumann reaction orafter completion of said reaction. As said aqueous medium solution, theSchotten-Baumann reaction mixture can be generally used as such. Thus,for instance, the reaction mixture obtained after carrying out theSchotten-Baumann reaction at a pH of about 7 to 12 or the reactionmixture obtained after carrying out the Schotten-Baumann reaction inaccordance with the present invention can suitably be used as such.

In that case, the above-mentioned Schotten-Baumann reaction and theactive-carbon treatment can also be performed simultaneously. In thiscase, it is sufficient that an adequate amount of active carbon becaused to coexist, at a time optionally selected, in the reaction systemfor carrying out the so-far known Schotten-Baumann reaction between theD-α-methyl-β-acylthiopropionic acid halide (1) orDL-α-methyl-β-acylthiopropionic acid halide and L-proline in an aqueousmedium. However, it is preferable, from the viewpoint of suppressing theadsorption loss of the D-α-methyl-β-acylthiopropionic acid halide (1) orDL-α-methyl-β-acylthiopropionic acid halide, to add during the latterhalf of the reaction period.

The above-mentioned aqueous medium solution to be subjected toactive-carbon treatment is generally the reaction mixture obtained bycarrying out the Schotten-Baumann reaction under conditions selectedfrom among the following: the mole ratio of the above-mentioned acidhalide (1) to L-proline (2)=about 0.5 to 1.2; pH 7 to 12; and reactiontemperature not higher than 10° C. However, the reaction conditions arenot limited to those mentioned above.

The above-mentioned active-carbon treatment is preferably carried out inan inert atmosphere, such as a nitrogen atmosphere, so that theformation of oxidized by-product can be restricted to a minimum.

The above-mentioned active-carbon treatment according to the presentinvention, if conducted using active carbon in combination with anorganic solvent, will be ineffective but, when carried out using activecarbon in combination with an aqueous medium, in particular water,produces an unexpectedly marked effect. Thus, said treatment is veryadvantageous in that it can be carried out in water without using anyorganic solvent.

The above-mentioned active-carbon treatment can also be used in a methodof purifying the N-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) orN-(DL-α-methyl-β-acylthiopropionyl)-L-proline, which contains suchimpurity precursors as represented by the above general formula (5) orformula (6), to give a high purity product. In this case, the medium canbe an aqueous one as in the case of the above-mentioned Schotten-Baumannreaction mixture.

The above-mentioned active-carbon treatment in accordance with thepresent invention results not only in removal of the precursors of N-α-methyl-β-(β-methyl-β-hydroxycarbonyl)-ethylthiopropionyl!-L-proline(7) but also in removal of the unreacted D-α-methyl-β-acylthiopropionicacid halide (1), which has an inhibitory effect on the crystallizationof captopril in aqueous medium, and the by-productD-α-methyl-β-acylthiopropionic acid formed by hydrolysis, so that thecrystallization of captopril in aqueous medium becomes very easy andhigh quality captopril can be obtained. Thus, a continuous process inaqueous medium comprising, for example, Schotten-Baumannreaction→active-carbon treatment→deacylation reaction→captoprilcrystallization, which process does not require isolation of theN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3), or, in other words, aproduction process by which very high quality captopril can be isolatedand obtained in an easy and simple and efficient manner can be realized.

It is of course possible as well to extract theN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) orN-(DL-α-methyl-β-acylthiopropionyl)-L-proline from the solution afterthe above-mentioned active-carbon treatment using an organic solventsuch as ethyl acetate or methylene chloride.

In another embodiment of the present invention, for obtaining captoprilwith a very low content of impurities such as N-α-methyl-β-(β-methyl-β-hydroxycarbonyl)-ethylthiopropionyl!-L-proline(7), the compounds of the above general formula (5) and the compound ofthe above formula (6), which are precursors of the compound of the aboveformula (7), can be removed by causing the above-mentionedN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) orN-(DL-α-methyl-β-acylthiopropionyl)-L-proline to crystallize out fromthe aqueous medium solution after completion of the above-mentionedSchotten-Baumann reaction at 35° C. to 100° C. under acidic conditions.

The aqueous medium solution to be used in the above crystallization isnot limited to any particular species but may be, for example, thereaction solution or post-treatment solution obtained after theSchotten-Baumann reaction carried out by the prior art methods or afterthe Schotten-Baumann reaction or active-carbon treatment in accordancewith the present invention, or an aqueous medium solution of theN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) orN-(DL-α-methyl-β-acylthiopropionyl)-L-proline once isolated in the formof an oil or crystals. In cases other than the crystallization from thereaction mixture, the same medium as mentioned hereinabove as theaqueous medium for carrying out the Schotten-Baumann reaction can beused.

The above-mentioned crystallization can be effected by first warming andthen adjusting to the conditions mentioned above by acidification andcooling. The pH in the step of warming is preferably not higher than 11,more preferably within the range of 1 to 10, most preferably within therange of 2 to 9. The warmed aqueous medium solution is then acidifiedand/or cooled as necessary so that theN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) orN-(DL-α-methyl-β-acylthiopropionyl)-L-proline can crystallize out at atemperature of 35° C. to 100° C. and a pH of 4.5 or below. When the pHis higher than 4.5, the deposition of crystals is insufficient and theyield becomes low.

Thus, for instance, when a solution with a pH not lower than about 5 orthe Schotten-Baumann reaction mixture approximately at neutral issubjected to the crystallization step, the crystallization is effectedat a final pH of about 4.5 or below, generally at a pH of 3.5 or below,preferably at a pH of about 1 to 3. A pH of 2 or below is preferred tomaximize the yield of crystals. The rate of the above-mentionedacidification is not limited to any particular level but, for producingthe effects of the present invention to the full, the rate of change inpH from the time of start of crystallization (the crystallizationgenerally starts at pH of 3.5 to 4.5) should preferably be about 0.4 pHunit or lower, more preferably about 0.2 pH unit or lower, per about 15minutes so that the above-mentioned precursors can be removedefficiently and good crystal growth can be secured. The pH at which theabove-mentioned crystallization starts may vary depending on the yieldof the Schotten-Baumann reaction, however.

The above-mentioned crystallization is effected at a temperature notlower than about 35° C., preferably not lower than about 40° C., morepreferably not lower than about 45° C. in particular at a temperaturenot lower than about 50° C. Excessively high temperatures, however,cause separation of the N-(D-α-methyl-β-acylthiopropionyl)-L-proline (3)or N-(DL-α-methyl-β-acylthiopropionyl)-L-proline as an oil. Consideringthis, an upper limit can readily be prescribed. Thus, it isrecommendable that the crystallization be effected at a temperature nothigher than about 100° C., preferably not higher than about 90° C., morepreferably not higher than about 70° C. When the temperature is too low,the elimination of the above-mentioned precursors may become very poorlyeffective and/or the characteristics of crystals may becomedeteriorated. Hence, the above range is recommended. In the case ofN-(D-α-methyl-β-acetylthiopropionyl)-L-proline (3), the crystallizationis suitably carried out generally at about 35° C. to 70° C. preferablyat about 40° C. to 70° C., more preferably at about 45° C. to 65° C., inparticular at about 50° C. to 60° C.

The acid or base to be used for pH adjustment in the abovecrystallization is not limited to any particular species but includessuch mineral acids as hydrochloric acid and sulfuric acid, and suchinorganic bases as sodium hydroxide, potassium hydroxide, lithiumhydroxide, sodium carbonate, potassium carbonate, lithium carbonate,sodium hydrogencarbonate, potassium hydrogencarbonate and lithiumhydrogencarbonate. Furthermore, where appropriate, bases capable offorming salts with the carboxyl group of theN-(α-methyl-β-acylthiopropionyl)-L-proline (3) and thereby increasingthe solubility thereof, including organic bases such as amines may alsobe used. These acids and bases may be used singly or two or more of themmay be used in combination. Among them, preferred acids are hydrochloricacid and sulfuric acid, and preferred bases are sodium hydroxide,potassium hydroxide and lithium hydroxide.

In the above-mentioned crystallization, an alternative operation ofcrystallization may also be employed which comprises cooling an acidicaqueous solution containing theN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) orN-(DL-α-methyl-β-acylthiopropionyl)-L-proline in an oily state.

In the above case, an aqueous medium solution containing theN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) orN-(DL-α-methyl-β-acylthiopropionyl)-L-proline, such as theSchotten-Baumann reaction mixture, is heated, for example, to atemperature not lower than about 60° C. to 70° C. and an acid or acidsolution is added at an arbitrary rate to the solution to reduce the pHto 4 to 5 or below, preferably about 3.5 or below so that the separationis caused as an oil, or an aqueous medium slurry containing theN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) orN-(DL-α-methyl-β-acylthiopropionyl)-L-proline with a pH of 4 to 5 orbelow, preferably about 3.5 or below is heated to a temperature notlower than about 60° C. to 70° C. to cause conversion to an oily state.The oily above-mentioned solution is then cooled, whereupon theN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) orN-(DL-α-methyl-β-acylthiopropionyl)-L-proline crystallizes.

The rate of cooling in the above procedure is not particularly limitedbut, for producing the effects of the present invention to the full, thecooling in the crystallization step is preferably conducted at a rate ofchange of about 1° C. or less, preferably about 0.5° C. or less, perabout 15 minutes so that the above-mentioned precursor can be removedefficiently and good crystal growth can be secured. In the case ofN-(D-α-methyl-β-acetylthiopropionyl)-L-proline (3), the crystallizationis generally caused by cooling to about 65° C. or below.

The above-mentioned method of crystallization generally gives a yield ofabout 80% to 90% or higher. For finally increasing the yield to about90% to 95% or even higher, the solution can be cooled to about 30° C. orbelow. For decreasing the solubility of theN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3), the crystallizationprocedure may include causing an inorganic salt such as sodium chlorideto coexist in the solution.

As is detailedly mentioned later herein, when the crystallization iseffected at low temperatures, not only the impurities such as theabove-mentioned precursor substance of N-α-methyl-β-(β-methyl-β-hydroxycarbonyl)ethylthiopropionyl!-L-proline(7), are difficult to eliminate but also minute crystals deposit orprecipitate to convert the system into a whippy slurry, which worsensthe fluidity or filtrability. The thus-obtained crystals have a highliquid content, are difficult to handle and are rather resistant todrying. These are serious problems in commercial production ofcaptopril. On the contrary, the method of crystallization according tothe present invention gives crystals which are not only highly pure butalso are satisfactorily rod-like, hence produces additional effects inthat the fluidity and filtrability of the slurry are very good and theliquid content is also low. Thus, the present invention can provide aexcellent method of crystallization from the industrial productionviewpoint. The case in which the whippy slurry obtained is subjected toheating treatment in the above manner also falls within the scope of thepresent invention. Needless to say, in this case, too, not only thequality but also the fluidity and filtrability of the slurry, and theliquid content of crystals, among others, can be improved.

In the crystallization method according to the present invention, theconcentration of the N-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) orN-(DL-α-methyl-β-acylthiopropionyl)-L-proline relative to the aqueousmedium is not particularly limited. From the viewpoints of productivity,yield and slurry fluidity, among others, however, a concentration ofabout 15% to about 30% (w/v) is generally employed. When thecrystallization is effected at room temperature on said concentration, awhippy slurry substantially lacking fluidity results and seriouslyreduces the operability on a commercial scale.

For preventing the formation of oxidated by-products, thecrystallization step according to the invention is preferably carriedout in an inert atmosphere, for example a nitrogen atmosphere.

Furthermore, when that reaction mixture or post-treatment mixturecontaining the N-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) with alow content of the above-mentioned precursor substances and otherimpurities as obtained by carrying out the reaction method or treatmentmethod under those Schotten-Baumann reaction conditions or active-carbontreatment conditions detailedly described later herein, or thosecrystals are used, the N-(D-α-methyl-β-acylthiopropionyl)-L-proline (3)with an even higher quality can be obtained. Furthermore, when anactive-carbon-treated solution, from which not only the precursors of N-α-methyl-β-(β-methyl-β-hydroxycarbonyl)-ethylthiopropionyl!-L-proline(7) but also the unreacted D-α-methyl-β-acylthiopropionic acid halide(1) or DL-α-methyl-β-acylthiopropionic acid halide and the hydrolysisby-product D-α-methyl-β-acylthiopropionic acid orDL-α-methyl-β-acylthiopropionic acid, among others, have been removed,is used, the N-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) orN-(DL-α-methyl-β-acylthiopropionyl)-L-proline can be obtained with avery high quality.

The crystallization method mentioned above can be efficiently used in amethod of purifying the N-(D-α-methyl-β-acylthiopropionyl)-L-proline (3)or N-(DL-α-methyl-β-acylthiopropionyl)-L-proline contaminated with suchimpurity precursor substances as the compounds of general formula (5) orformula (6) to give a high purity product. As the medium in this case,an aqueous medium can be used as well as the above-mentionedSchotten-Baumann reaction mixture.

Since the crystallization method according to the present invention hasan operability-improving effect as mentioned above, it is needless tosay that said method can also be effectively applied, for instance, tothe N-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) orN-(DL-α-methyl-β-acylthiopropionyl)-L-proline free of theabove-mentioned precursor substances etc.

In another embodiment of the present invention, for obtaining captoprilwith a very low content of the impurity represented by N-α-methyl-β-(β-methyl-β-hydroxycarbonyl)-ethylthiopropionyl!-L-proline(7), potassium hydrogencarbonate is used as the deacidifying condensingagent in the above Schotten-Baumann reaction. This is based on thefinding obtained by the present inventors that the use of potassiumhydrogencarbonate can lead to marked suppression of the formation of theabove-mentioned compounds of general formula (5) and formula (6), whichare precursors of the above-mentioned compound of formula (7). Ascompared with other alkali metal carbonates such as sodium carbonate,potassium carbonate, lithium carbonate and sodium hydrogencarbonate andother inorganic bases and organic bases, potassium hydrogen-carbonatewas found to be an excellent deacidifying condensing agent not onlyspecifically effective in preventing the formation of the compoundsmentioned above but capable of being charged to a high concentration andleading to the formation of theN-(D-α-methyl-β-acylthiopropionyl)-L-proline in high yields.

In addition, the use of potassium hydrogencarbonate as the deacidifyingcondensing agent in the Schotten-Baumann reaction makes it possible tomaintain the pH during reaction within the range of 7.3 to 10.2,preferably 7.5 to 9.0, which is desirable for preventing the formationof the above-mentioned precursors of compound (7), namely the compoundsof general formula (5) and formula (6), without requiring pH controlwith a strong alkali such as sodium hydroxide or potassium hydroxidebefore starting the reaction and in the course thereof. Since, thus, nospecial pH control procedure is essentially required during thereaction, a very easy and simple process for synthesizing high puritycaptopril can be provided.

In carrying out the Schotten-Baumann reaction using potassiumhydrogencarbonate as the deacidifying condensing agent according to thepresent invention, the mole ratio between theD-α-methyl-β-acylthiopropionic acid halide (1) orDL-α-methyl-β-acylthiopropionic acid halide and potassiumhydrogencarbonate is desirably not less than 1.6, preferably not lessthan 2.0, and the mole ratio between said acid halide and L-proline isdesirably 0.7 to 1.1, preferably 1. Generally, the reaction is carriedout at a temperature of about 10° C. or below but not causing freezingof the solution. No particular limitations are imposed on the chargedconcentrations but, generally, L-proline is used in a proportion ofabout 10 to 100% (w/v) relative to the solvent.

The reaction solvent may be water alone or a combination of water and anorganic solvent. In the latter case, from the organic solvent recoveryand other viewpoints, an organic solvent immiscible with water may beused to provide a heterogeneous two-layer system.

The reaction is caused to proceed by adding theD-α-methyl-β-acylthiopropionic acid halide (1) orDL-α-methyl-β-acylthiopropionic acid halide (hereinafter, theD-α-methyl-β-acylthiopropionic acid halide (1) orDL-α-methyl-β-acylthiopropionic acid halide is sometimes referred tomerely as "acid halide") to an aqueous medium containing L-proline (2).The deacidifying condensing agent potassium hydrogencarbonate may beadded either in advance to the aqueous medium prior to the addition ofacid halide, or successively or portionwise simultaneously with theaddition of acid halide. Preferably, the unreacted acid halide is notallowed to remain in the system for a long period.

The deacidifying condensing agent potassium hydrogencarbonate may beused either by itself or in combination with such an inorganic base assodium hydroxide, potassium hydroxide, lithium hydroxide, sodiumcarbonate, lithium carbonate or sodium hydrogencarbonate, or such anorganic base as pyridine or triethylamine, for instance.

The above-mentioned embodiments of the present invention, namely theactive-carbon treatment of an aqueous medium solution of theN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) at a pH not higher than12, the crystallization of theN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) from an aqueous mediumsolution thereof at 35° C. to 100° C. under acidic conditions, and theuse of potassium hydrogencarbonate as the deacidifying condensing agentin the Schotten-Baumann reaction between the acid halide and L-proline,may of course be employed either individually or combinedly.

In the following, those modes for carrying out the Schotten-Baumannreaction which is suited for application of the present invention isdescribed in detail.

The D-α-methyl-β-acylthiopropionic acid halide (1) orDL-α-methyl-β-acylthiopropionic acid halide to be used as a startingsubstance in the Schotten-Baumann reaction can be prepared, for exampleby those processes described in Japanese Kokai Publication Sho-55-38386,Sho-55-118455 and Hei-1-222798, Japanese Kokoku PublicationSho-61-30666, and Chem. Phar. Bull., 30 (9), 3139-3146 (1982). In suchprocesses, for example, the corresponding carboxylic acid, namelyD-α-methyl-β-acylthiopropionic acid or DL-α-methyl-β-acylthiopropionicacid is first prepared and it is then treated with a halogenatingreagent such as thionyl chloride, oxalyl dichloride, phosphorustrichloride, phosphorus tribromide or thionyl bromide.D-α-methyl-β-acylthiopropionyl chlorides orDL-α-methyl-β-acylthiopropionyl chlorides which can readily be preparedby using thionyl chloride, among others, can be preferably used in thepractice of the present invention. As the acyl group of saidD-α-methyl-β-acylthiopropionic acid halide (1) orDL-α-methyl-β-acylthiopropionic acid halide, there may be mentionedacetyl, propionyl, benzoyl and the like. Among them, acetyl ispreferred.

For preventing, in the Schotten-Baumann reaction, the formation of thecompounds of general formula (5) and formula (6), which are precursorsof the impurity of formula (7), the following conditions are desirable:pH of 7.3 to 10.2, temperature of about 10° C. or below but not causingfreezing the solution, intensity of stirring of at least 0.1 kW/m³, andacid halide (1)/L-proline (2) mole ratio of 0.7 to 1.1, preferably 1. Incases where the D-α-methyl-β-acylthiopropionic acid halide (1) issubmitted to the reaction in the form of DL-α-methyl-β-acylthiopropionicacid halide, the DL-form is used in an amount of 0.7 to 1.1 moles permole of L-proline (2).

The charged concentrations are not particularly limited but, generally,about 10 to 100% (w/v) relative to the solvent as expressed in terms ofL-proline concentration is used.

The reaction solvent may be water, which is a basic aqueous media, byitself or a combination of water and an organic solvent. In this case,from the organic solvent recovery viewpoint, among others, an organicsolvent immiscible with water may be used to thereby provide aheterogeneous two-layer system.

The reaction is effected by adding the D-α-methyl-β-acylthiopropionicacid halide (1) or DL-α-methyl-β-acylthiopropionic acid halide to abasic aqueous medium containing L-proline (2) and a deacidifyingcondensing agent. The deacidifying condensing agent is used in an amountmatched to the amount of the acid halide added, and is added eithersuccessively or portionwise. Preferably, the unreacted acid halide isnot allowed to remain in the system for a long period.

As said deacidifying condensing agent, there may be mentioned inorganicbases such as sodium hydroxide, potassium hydroxide, lithium hydroxide,sodium carbonate, potassium carbonate, lithium carbonate, sodiumhydrogencarbonate and potassium hydrogencarbonate as well as organicamines such as pyridine, triethylamine and the like.

In the following, the above-mentioned pH condition and stirringintensity are detailedly explained.

In carrying out the Schotten-Baumann reaction in the practice of thepresent invention, pH 7.3 to 10.2 is employed as the pH when the acidhalide is added to a basic aqueous solution containing L-proline (2) anda deacidifying condensing agent. The pH is preferably 7.5 to 10.0, morepreferably 8.0 to 9.8. The pH may be that basicity which is obtainedwith the deacidifying condensing agent. Any other basic substance havingbuffer action may be caused to coexist. When the pH is too low, the acidhalide may be hydrolyzed to give the corresponding carboxylic acid, etc.as by-products, resulting in decreased yields. If the pH is excessivelyhigh, by-products such as the N-acyl-L-proline,N-(D-α-methyl-β-mercaptopropionyl)-L-proline (4) orN-(DL-α-methyl-β-mercaptopropionyl)-L-proline and further theabove-mentioned compounds of general formula (5) or formula (6), i.e.precursors of N-α-methyl-β-(β-methyl-β-hydroxycarbonyl)ethylthiopropionyl!-L-proline (7)tend to be formed in increased amounts. For preventing the formation ofthese by-products and securing high quality and high yields, andparticularly for restricting the formation of N-α-methyl-β-(α-methyl-β-hydroxycarbonyl)ethylthiopropionyl!-L-proline(7), which gets into captopril and is difficult to remove, in itsprecursor stage to a minimum, it is necessary that the pH be maintainedin the above-mentioned range.

The intensity of stirring in the step of adding the acid halide to abasic aqueous solution containing L-proline (2) and a deacidifyingcondensing agent and allowing the reaction to proceed, is generally notless than about 0.1 kW/m³, preferably not less than 0.2 kW/m³, morepreferably not less than about 0.5 kW/m³, especially not less than about1.0 kW/m³. While a greater stirring intensity is desirable, the capacityof the stirrer serves as a restricting factor and, generally, there isan upper limit of about 5 kW/m³. When the stirring intensity is belowthe above-mentioned value, various side reactions such as hydrolysis ofthe acid halide and formation of the above-mentioned compounds offormula (5) and formula (6), which are precursors of N-α-methyl-β-(β-methyl-β-hydroxycarbonyl)ethylthiopropionyl!-L-proline (7)are apt to occur, hence the proportion of the desired main reactionbetween the acid halide and L-proline (2) decreases. By maintaining theabove-mentioned stirring intensity, the formation of the above-mentionedcompounds of formula (5) and formula (6), which are precursors of N-α-methyl-β-( -methyl-β-hydroxycarbonyl)-ethylthiopropionyl!-L-proline(7), and other by-products can be suppressed.

In the following, deacylation reaction modes suited for the practice ofthe present invention are described in detail.

In the practice of the present invention, theN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) obtained by theabove-mentioned Schotten-Baumann reaction is further deacylated. Whenthe D-α-methyl-β-acylthiopropionic acid halide (1) is subjected to theSchotten-Baumann reaction in the form of DL-α-methyl-β-acylthiopropionicacid halide, the N-(DL-α-methyl-β-acylthiopropionyl)-L-proline obtainedis subjected to optical resolution and the resulting D-form, namelyN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) is further deacylated.Irrespective of the experience of optical resolution, saidN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) is preferably oneobtained after the active-carbon treatment according to the presentinvention and/or the crystallization according to the present invention.Particularly when a D-α-methyl-β-acylthiopropionic acid halide (1) isused as the acid halide, those crystals that are once collected bysubjecting the reaction mixture solution from the above-mentionedSchotten-Baumann reaction as such or after active-carbon treatment inthe vicinity of neutral to crystllization treatment at a temperature of35° C. or above under acidic conditions at a pH of 4.5 or below,preferably pH of 3.5 or below can be preferably used, optionally afterstorage.

In the above-mentioned deacylation reaction step, since N-α-methyl-β-(β-methyl-β-hydroxycarbonyl)ethylthiopropionyl!-L-proline (7)is formed from the above-mentioned compounds of general formula (5) andformula (6), among others, it is desirable that the reaction mode beselected so as to minimize the formation of said compound (7).Therefore, in accordance with the present invention, the above-mentioneddeacylation reaction is carried out in an alkaline aqueous medium. Asthe aqueous medium, use can be made of the same aqueous medium as thatused in the Schotten-Baumann reaction. Thus, it is possible to carry outthe Schotten-Baumann reaction, active-carbon treatment and deacylationin one and the same reaction vessel.

From the viewpoint of inhibiting impurity formation, the alkali to beused in the above deacylation reaction is preferably an alkali metalhydroxide such as sodium hydroxide, potassium hydroxide or lithiumhydroxide. These may be used each alone or two or more of them may beused combinedly.

As regards the amount of the above-mentioned alkali, generally, it isconveniently used, in the case of sodium hydroxide, in a concentrationof about 30% by weight or higher in aqueous solution.

The pH to be employed in the above deacylation reaction is not less than8, although it depends on the reaction temperature. For minimizing theformation of N-α-methyl-β-(β-methyl-β-hydroxycarbonyl)ethylthiopropionyl!-L-proline (7)from the above-mentioned precursors, it is recommendable to employ a pHnot less than about 13, preferably a pH not less than about 13.5, morepreferably not less than about 14.

As mentioned above, the reaction pH and the method of addition areimportant factors in preventing, among others, the formation of N-α-methyl-β-(β-methyl-β-hydroxycarbonyl)ethylthiopropionyl!-L-proline (7)from the above-mentioned precursors during the deacylation reaction inthe practice of the present invention.

As a typical deacylation reaction method, there may be mentioned, forexample, the one which comprises using the reaction mixture containing,in the above-mentioned alkaline aqueous medium, theN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) together with theabove-mentioned compounds of general formula (5) or formula (6), whichare precursors of N-α-methyl-β-(β-methyl-β-hydroxycarbonyl)-ethylthiopropionyl!-L-proline(7), or the active-carbon-treated solution, or crystals obtainedtherefrom and maintaining the pH at about 13 or higher until completionof the reaction. In this case, said alkaline aqueous medium may containa required amount of alkali added in advance, or a required amount ofalkali may be added successively or portionwise with the progress of thereaction to thereby maintain the pH at a desired level. Generally, byreason of simplicity, the former is preferred.

In the practice of the present invention, the deacylation reaction canbe carried out at 70° C. or below, preferably at 50° C. or below and,generally, said reaction is carried out at around room temperature orbelow. For removing the heat generated, it is also desirable to cool, inadvance, the reaction solution and/or the alkaline aqueous medium to beused.

When the deacylation reaction is carried out in an inert atmosphere suchas a nitrogen atmosphere, the formation of oxidated by-products such asthe disulfide can be suppressed to a level at which no problem isencountered at all. Therefore, in particular, such restriction of thealkali concentration in the step of deacylation as described in JapaneseKokai Publication Hei-3-169856 is unnecessary.

In the above-mentioned deacylation reaction, the reactant concentrationsare not particularly limited but, for increasing the deposition ofcaptopril in the crystallization step, said reaction is preferablycarried out at a high N-(D-α-methyl-β-acylthiopropionyl)-L-proline (3)concentration of about 20 to 100% (w/v) relative to the aqueous medium.

In accordance with the present invention, high qualityN-(D-α-methyl-β-mercaptopropionyl)-L-proline (4) (captopril) can beobtained in high yields by subjecting theN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) obtained in the abovemanner by the Schotten-Baumann reaction to deacylation reaction in analkaline aqueous medium and then, after acidification, causingcrystallization of N-(D-α-methyl-β-mercaptopropionyl)-L-proline (4)(captopril) from the reaction mixture in aqueous medium, as detailedlymentioned hereinabove.

In particular, as mentioned above, the Schotten-Baumann reaction mixtureor active-carbon-treated solution containing anN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) as theN-(α-methyl-β-acylthiopropionyl)-L-proline as obtained in accordancewith the present invention contains various coexisting impurities atlower levels as compared with the reaction mixture obtained by theSchotten-Baumann reaction carried out in the conventional manner and,therefore, said reaction mixture or treated solution can be subjected assuch to deacylation reaction without isolation of theN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3), and the subsequentacidification can result in crystallization of high quality captopril inaqueous medium, in particular in aqueous solution. In particular, incase of the active-carbon-treated solution, not only the precursors ofN- α-methyl-β-(β-methyl-β-hydroxycarbonyl)ethylthiopropionyl!-L-proline(7) but also the unreacted D-α-methyl-β-acylthiopropionic acid halide(1) and the hydrolysis by-product D-α-methyl-β-acylthiopropionic acid,among others, which have an inhibitory effect on the crystallization ofcaptopril in aqueous medium are removed and, therefore, thecrystllization of captopril in aqueous medium is very easy and highquality captopril can be obtained. Thus, it is possible to realize acontinuous process in aqueous medium, such as a process Schotten-Baumannreaction→deacylation reaction→captopril crystallization, orSchotten-Baumann reaction→active-carbon treatment→deacylationreaction→captopril crystallization, which process does not require theisolation of N-(D-α-methyl-β-acylthiopropionyl)-L-proline (3), namely aproduction process in which high quality captopril can be obtained byisolation in a simple and easy and efficient manner. It is no morenecessary to extract and purify captopril using an organic solvent asdescribed in Japanese Kokai Publication Hei-4-305565, Hei-5-17435,Hei-5-221966, etc.

In the practice of the present invention, for increasing the depositionof captopril in the step of captopril crystallization, the salting-outeffect may be utilized as necessary; for example, an inorganic salt suchas sodium chloride, potassium sulfate or lithium sulfate may be added orcaused to be formed in the system, as described in Japanese KokaiPublication Sho-55-32063 and Hei-3-169856, for instance, or thecaptopril concentration and salt concentration may be increased byconcentrating the system to a certain extent. On the other hand, amethod may be applied to the present invention, in which thecrystallization is caused by acidifying the system to a pH of 3 orbelow, preferably about 2 or below, at about 20° C. to 45° C. bygradually adding a mineral acid, such as hydrochloric acid, for exampleconcentrated hydrochloric acid, or sulfuric acid, for example sulfuricacid with a concentration of at least about 50% or concentrated sulfuricacid so as to prevent captopril from becoming oily, and, finally, thesystem is cooled to about 0° C. to 5° C. to thereby increase thedeposition. The thus-deposited captopril crystals are collected byfiltration or centrifugation and generally dried under vacuum.

As detailedly described hereinabove, by employing the steps of:

1 carrying out the Schotten-Baumann reaction under specified conditions;

2 treating the Schotten-Baumann reaction mixture or crystals of thecompound of general formula (3) with active carbon in the vicinity ofneutral;

3 subjecting the Schotten-Baumann reaction mixture, either as such orafter active-carbon treatment in the vicinity of neutral, tocrystallization under specified conditions, and then collecting and/orstoring the crystals; and

4 carrying out the deacylation under specific conditions in an aqueousmedium containing at least one alkali selected from the group consistingof sodium hydroxide, potassium hydroxide and lithium hydroxide,

either singly or in combination, captopril superior in quality, forexample in terms of melting point, content and impurity content, tothose captopril bulk substances so far reported can be produced fromL-proline (2) and D-α-methyl-β-acetylthiopropionyl chloride in highyields not less than 75 mole percent and at low cost.

BEST MODES FOR CARRYING OUT THE INVENTION

The following examples are intended to describe the present invention infurther detail and should by no means be construed as defining the scopeof the invention.

In the following examples and reference examples,D-α-methyl-β-acetylthiopropionyl chloride was used as saidD-α-methyl-β-acylthiopropionic acid halide (1) andN-(D-α-methyl-β-acetylthiopropionyl)-L-proline was used as saidN-(α-methyl-β-acylthiopropionyl)-L-proline (3).

Furthermore, in the following examples and reference examples, all theprocedures other than filtration, rinsing of crystals and downstreamprocedures were carried out under nitrogen atmosphere.

Moreover, in the examples and reference examples, the compound ofgeneral formula (5) and the compound of formula (6) are referred tobriefly as compound (5) and compound (6), respectively. It should alsobe understood that in the examples and reference examples, the acylgroup of compound (5) is acetyl.

EXAMPLES 1, 2, AND 3 AND REFERENCE EXAMPLE 1

To 101 g of deionized water was added 19.0 g (0.165 mol) of L-proline,and after cooling to about 5° C. and under agitation, a 30 wt. % aqueoussolution of NaOH was added dropwise slowly to adjust the mixture to pH9.5 to 9.9 at about 0° C. to 3° C. Under nitrogen gas and with theabove-mentioned pH maintained, 29.2 9 (0.162 mol) ofD-α-methyl-β-acetylthiopropionyl chloride was added dropwise over 1 hourat 0° C. to 3° C. with stirring at the agitation intensity indicated inTable 1. After completion of dropwise addition, the reaction was furthercontinued until the consumption of a 30 wt. % aqueous solution of NaOHhad ceased almost completely. The yields of various products in thisreaction mixture are shown in Table 1. In Table 1, product 1 meansN-acetyl-L-proline, product 2 means captopril, product 3 means compound(6), product 4 means compound (5)(n=2), and product meansN-(D-α-methyl-β-acetylthiopropionyl)-L-proline. As shown in Table 1, theyield of product 5 is the molar yield based onD-α-methyl-β-acetylthiopropionyl chloride, the yields of products 1, 2,and 4 are weight percents relative to product 5, and the yield ofproduct 3 is the area % relative to product 5.

                  TABLE 1    ______________________________________    Agitation    intensity     Product    (kW/m.sup.3)  1      2       3       4    5    ______________________________________    Reference            <0.05     13%    3.3%  0.5     6%   70%    Example 1    Example 1            ca. 0.1   5%     0.4%  Not     3%   90%                                   Detected    Example 2            0.2 to 0.4                      2%     0.2%  Not     2%   95%                                   Detected    Example 3            1.3 to 1.5                      1%     0.2%  Not     1%   97%                                   Detected    ______________________________________

EXAMPLE 4, 5, 6, 7, AND 8 AND REFERENCE EXAMPLE 2

To 101 g of deionized water was added 19.0 g (0.165 mol) of L-proline,and after cooling to about 5° C. and under agitation, a 30 wt. % aqueoussolution of NaOH was added dropwise slowly at about 0° C. to 3° C. toadjust the mixture to the pH indicated in Table 2. Under nitrogen andwith the above-mentioned pH maintained, 29.21 g (0.162 mol) ofD-α-methyl-β-acetylthiopropionyl chloride was added dropwise over 1 hourat 0° C. to 3° C. with stirring at the agitation intensity of about 1kW/m³. After completion of dropwise addition, the reaction was furthercontinued until the consumption of a 30 wt. % aqueous solution of NaOHhad ceased almost completely. The yields of various products in thisreaction mixture are shown in Table 2. In Table 2, each of products 1 to5 means the same as in Table 1. The yields of products 1 to 5 in Table 2are as defined in Table 1. The yield ratio of compound (5)(n=3 and 4) toproduct 4 namely, compound (5)(n=2)! was not more than 2 area % inExamples 4, 5, 6, 7, and 8 and not more than 6 area % in ReferenceExample 2.

                  TABLE 2    ______________________________________              Product    pH          1       2       3      4     5    ______________________________________    Example 4           7.4 to 7.9                    0.4%    0.2%  Not    0.5%  89%                                  Dectected    Example 5           8.1 to 8.6                    0.6%    0.2%  Not    0.7%  91%                                  Detected    Example 6           8.8 to 9.3                    0.7%    0.2%  Not    0.7%  96%                                  Detected    Example 7           9.0 to 9.6                    1.0%    0.2%  Not    0.9%  99%                                  Detected    Example 8           9.8 to   1.7%    0.3%  Not    1.5%  97%           10.2                   Detected    Reference           10.3 to  4.8%    0.6%  0.2%   4.1%  92%    Example 2           10.6    ______________________________________

EXAMPLE 9 AND REFERENCE EXAMPLES 3, 4, 5, AND 6

The Schotten-Baumann reaction mixture obtained in the same manner asExample 7 was adjusted to pH 7 by adding a 35 wt. % aqueous solution ofHCl slowly under agitation at about 3° C. To 9.75 g of this aqueoussolution which contained 2.0 g ofN-(D-α-methyl-β-acetylthiopropionyl)-L-proline together with 1.2 wt. %of compound (5)(n=2) based onN-(D-α-methyl-β-acetylthiopropionyl)-L-proline! was added 0.6 g of theadditive shown in Table 3 and the mixture was stirred at roomtemperature for about 30 minutes. The additive was then filtered off andwashed with about 6 ml of deionized water. The filtrate thus obtainedwas analyzed for the proportion of compound (5)(n=2) relative toN-(D-α-methyl-β-acetylthiopropionyl)-L-proline. The results arepresented in Table 3. Incidentally, the recovery rate ofN-(D-α-methyl-β-acetylthiopropionyl)-L-proline was invariably close to100 wt. %.

                  TABLE 3    ______________________________________                           Compound (5)                  Additive (n = 2) content    ______________________________________    Example 9       Active carbon                               0.3 wt. %    Reference Example 3                    Active clay                               1.2 wt. %    Reference Example 4                    Celite     1.2 wt. %    Reference Example 5                    Alumina    1.2 wt. %    Reference Example 6                    Silica gel 1.2 wt. %    ______________________________________

EXAMPLE 10

Following the Schotten-Baumann reaction betweenD-α-methyl-β-acetylthiopropionyl chloride and L-proline in aqueousmedium, 2.0 g of the harvested crystals ofN-(D-α-methyl-β-acetylthiopropionyl)-L-proline which contained 2.0 wt. %of compound (5)(n=2) based onN-(D-α-methyl-β-acetylthiopropionyl)-L-proline! were added to 25 ml ofdeionized water and the mixture was adjusted to pH 7 and dissolved byadding a 30 wt. % aqueous solution of NaOH slowly under agitation. Tothe resulting aqueous solution was added 0.7 g of active carbon and themixture was stirred at room temperature for about 30 minutes. The carbonwas then filtered off and washed with about 6 ml of deionized water. Thefiltrate thus obtained was analyzed. The recovery rate ofN-(D-α-methyl-β-acetylthiopropionyl)-L-proline was approximately 99 wt.% and the proportion of compound (5)(n=2) relative toN-(D-α-methyl-β-acetylthiopropionyl)-L-proline was 0.5 wt. %.

REFERENCE EXAMPLE 7, 8, AND 9

The crystals of N-(D-α-methyl-β-acetylthiopropionyl)-L-proline as usedin Example 10 which contained compound (5) (n=2) in a proportion of 2.0wt. % relative to N-(D-α-methyl-β-acetylthiopropionyl)-L-proline!, 2.0grams, were dissolved in 25 ml of the solvent shown in Table 4. To thissolution was added 0.7 g of active carbon and the mixture was stirred atroom temperature for about 30 minutes. The carbon was then filtered offand the filtrate was analyzed. The proportion of compound (5)(n=2)relative to N-(D-α-methyl-β-acetylthiopropionyl)-L-proline after activecarbon treatment is shown in Table 4.

                  TABLE 4    ______________________________________               Solvent Compound (5) (n = 2) content    ______________________________________    Reference Example 7                 Toluene   2.3 wt. %    Reference Example 8                 Methanol  1.9 wt. %    Reference Example 9                 Etanol    1.7 wt. %    ______________________________________

EXAMPLES 11, 12, AND 13 AND REFERENCE EXAMPLE 10

The Schotten-Baumann reaction mixture obtained in the same manner asExample 6 was adjusted to pH 7 by adding a 35 wt. % aqueous solution ofHCl slowly under agitation at about 3° C. To 19.75 g of this aqueoussolution which contained 4.1 g ofN-(D-α-methyl-β-acetylthiopropionyl)-L-proline together with 0.8 wt. %of compound (5)(n=2) based onN-(D-α-methyl-β-acetylthiopropionyl)-L-proline! was added active carbonin the amount indicated in Table 5 and the mixture was stirred at roomtemperature for about 30 minutes. The active carbon was then filteredoff and washed with about 6 ml of deionized water. Under nitrogen, tothe filtrate obtained was added 4N-NaOH/water about 3.2 equivalentsbased on N-(D-α-methyl-β-acetylthiopropionyl)-L-proline! en bloc withstirring to make the pH not less than 13.1. This mixture was stirred atroom temperature for about 15 minutes and after the deacetylationreaction had been completed under the same conditions, the reactionmixture was analyzed to find the proportion of N-α-methyl-β-(β-methyl-β-hydroxycarbonyl)-ethylthiopropionyl!-L-proline(hereinafter referred to briefly as BA-CP) relative to captopril. Theresults are shown in Table 5.

                  TABLE 5    ______________________________________                  Amount of                  active carbon                          BA-CP content    ______________________________________    Reference Example 10                    --        0.31 wt. %    Example 11      0.41 g    0.13 wt. %    Example 12      0.82 g    0.07 wt. %    Example 13      1.64 g    Not detected    ______________________________________

EXAMPLES 14, 15, AND 16

The Schotten-Baumann reaction mixture obtained in the same manner asExample 7 was adjusted to pH 7 by adding a 35 wt. % aqueous solution ofHCl slowly at about 3° C. with stirring. This aqueous mixture, 50.0 gwhich contained 10.3 g of N-(D-α-methyl-β-acetylthiopropionyl)-L-prolinetogether with 1.3 wt. % of compound (5)(n=2) based onN-(D-α-methyl-β-acetylthiopropionyl)-L-proline and 1.2 wt. % ofN-acetyl-L-proline based onN-(D-α-methyl-β-acetylthiopropionyl)-L-proline! was heated and stirred.At the temperature indicated in Table 6, the mixture was acidified witha 35 wt. % aqueous solution of HCl to let crystals deposit. In Examples14 and 15, the 35 wt. % aqueous solution of HCl was added fast till pH 5and, then, dropwise so that the pH dropped by about 0.2 in every 15minutes till pH 3 to let crystals separate out gradually. Furthermore,the addition speed was gradually increased until the final pH 1.5 wasestablished. In Example 16, the 35 wt. % aqueous solution of HCl wasadded fast till pH 5 and seed crystals were added at pH 4.7. Then, theHCl solution was added dropwise slowly so that the pH would drop byabout 0.1 in every 15 minutes till pH 3 to let crystals separate outgradually. Then, the addition speed was gradually increased until thefinal pH 1.5 was established. The acidified mixture was allowed to coolgradually to room temperature and the gentle agitation was continued atroom temperature for about 1 hour. The crystals that had separated outwere harvested by filtration, rinsed with 23 ml of cold water,sufficiently drained, and dried in vacuo at about 40° C. Thecrystallization yield of the crystal obtained,N-(D-α-methyl-β-acetylthiopropionyl)-L-proline, and the proportions ofcompound (5)(n=2) and N-acetyl-L-proline are shown in Table 6.

                  TABLE 6    ______________________________________    Acidifica-    Crystal-   Compound  N-acetyl-    tion tem-     lization   (5) (n = 2)                                       L-proline    perature      yield      content   content    ______________________________________    Example 14            58 to 62° C.                      95%        0.3 wt. %                                         0.1 wt. %    Example 15            47 to 52° C.                      96%        0.5 wt. %                                         0.1 wt. %    Example 16            38 to 43° C.                      95%        0.7 wt. %                                         0.1 wt. %    ______________________________________

EXAMPLE 17

The same Schotten-Baumann reaction mixture as used in Examples 14, 15,and 16 (preadjusted to pH 7), 50.0 grams which contained 10.3 g ofN-(D-α-methyl-β-acetylthiopropionyl)-L-proline together with 1.3 wt. %of compound (5)(n=2) and 1.2 wt. % of N-acetyl-L-proline both based onN-(D-α-methyl-β-acetylthiopropionyl)-L-proline!, was heated to about 70°C. and acidified to pH about 3 with a 35 wt. % aqueous solution of HClunder agitation to let an oil separate out. Then, this mixture wasfurther acidified to pH 1.5. The mixture was cooled from 69° C. at therate of about 0.5° C. /15 min. to let crystals separate out graduallyunder intense agitation. After crystallization, the mixture was furthercooled and maintained at about 40° C. for 30 minutes. The mixture wasfurther cooled to room temperature with gentle stirring and, then,stirred gently at room temperature for about 1 hour. The crystals thathad separated out were harvested by filtration, rinsed with 23 ml ofcold water, drained well, and dried in vacuo at about 40° C. Thecrystallization yield of the crystal obtained,N-(D-α-methyl-β-acetylthiopropionyl)-L-proline, was 95% and theproportions of compound (5)(n=2) and N-acetyl-L-proline were 0.3 wt. %and 0.l wt. %, respectively.

EXAMPLE 18

The same Schotten-Baumann reaction mixture as used in Examples 14, 15,and 16 (preadjusted to pH 7), 50.0 grams which contained 10.3 g ofN-(D-α-methyl-β-acetylthiopropionyl)-L-proline together with 1.3 wt. %of compound (5)(n=2) and 1.2 wt. % of N-acetyl-L- proline both based onN-(D-α-methyl-β-acetylthiopropionyl)-L-proline!, was acidified to pH 1.5by adding a 35 wt. % aqueous solution of HCl at 22° C. to 25° C. withstirring to let crystals separate out. The addition of the 35 wt. %aqueous solution of HCl was carried out in the manner described inExample 12. After the final pH 1.5 was established, gentle agitation wascontinued at room temperature for about 1 hour. When a small amount ofthis whip-like slurry was recovered by filtration and washed with coldwater, the proportion of compound (5) (n=2) was found to be 12 wt. %.The above slurry was heated at about 75° C. to provide an oil. This oilwas cooled in the manner described in Example 17 to harvest crystals.The crystallization yield of the crystal obtained,N-(D-α-methyl-β-acetylthiopropionyl)-L-proline, was 95% and theproportions of compound (5)(n=2) and N-acetyl-L-proline were 0.4 wt. %and 0.1 wt. %, respectively.

REFERENCE EXAMPLE 11

The same Schotten-Baumann reaction mixture as used in Examples 14, 15,and 16 (preadjusted to pH 7), 50.0 grams which contained 10.3 g ofN-(D-α-methyl-β-acetylthiopropionyl)-L-proline together with 1.3 wt. %of compound (5)(n=2) and 1.2 wt. % of N-acetyl-L-proline both based onN-(D-α-methyl-β-acetylthiopropionyl)-L-proline!, was acidified to pH 1.5by adding a 35 wt. % aqueous solution of HCl thereto at 22° C. to 25° C.with stirring to let crystals separate out and gentle stirring wascontinued for about 1 hour at room temperature. The resulting whip-likeslurry was recovered by filtration, washed with 23 ml of cold water,drained well, and dried in vacuo at about 40° C. The crystallizationyield of N-(D-α-methyl-β-acetylthiopropionyl)-L-proline was 96% and theproportions of compound (5)(n=2) and N-acetyl-L-proline were 12 wt. %and 0.2 wt. %, respectively.

REFERENCE EXAMPLE 12

The filtrability of the slurries, liquid contents of the wet crystals,and crystal properties in Examples 14, 15, 16, 17, and 18 and ReferenceExample 11 were compared. The results are presented in Table 7.

                  TABLE 7    ______________________________________                      Liquid con-           Flow-through                      tent of wet           speed (m.sup.3 /m.sup.2 /h)                      crystal (on                                 Description of           A    B      C      a wet basis)                                       crystals    ______________________________________    Example 14             8.8    8.8    11.8 17 wt. % Glossy                                         large rods    Example 15             7.3    8.8    10.6 23 wt. % Glossy                                         large rods    Example 16             6.2    5.9    8.2  28 wt. % Glossy medium-                                         size rods    Example 17             10.6   10.6   10.6 17 wt. % Glossy                                         large rods    Example 18             8.8    11.8   11.8 18 wt. % Glossy                                         large rods    Reference             3.9    2.8    4.2  37 wt. % Small rods or    Example 11                           needless    ______________________________________

The slurry obtained in Reference Example 11 could be withdrawn only in avery long time. Therefore, the comparison of filtrability was made interms of the filtration speeds determined by the following threemethods. The flow-through speeds were evaluated by the same suctionfiltration method using a 40 mm (dia.) filter paper.

A: The wet cake was adjusted to a uniform thickness and the filtrate waspassed.

B: The wet cake was spread to drain sufficiently and the filtrate waspassed.

C: The wet cake was spread to drain sufficiently and 23 ml of cold waterwas passed.

EXAMPLES 19 AND 20

The same crystals of N-(D-α-methyl-β-acetylthiopropionyl)-L-proline asused in Example 10 which contained 2.0 wt. % of compound (5)(n=2)!, 2.0grams, were added to 20 ml of deionized water and the mixture wasadjusted to the pH shown in Table 8 by adding a 30 wt. % aqueoussolution of NaOH slowly under stirring. To the aqueous solution thusobtained was added 0.8 g of active carbon and the mixture was stirred atroom temperature for about 10 minutes. The carbon was then filtered offand washed with about 8 ml of deionized water. The filtrate was treatedin the same manner as described in Example 11 to let crystals separateout. The slurry thus obtained was washed with 10 ml of water, drainedwell, and-dried in vacuo at about 40° C. The proportion of compound(5)(n=2) in the crystal, N-(D-α-methyl-β-acetylthiopropionyl)-L-prolinethus obtained is shown in Table 8.

                  TABLE 8    ______________________________________               pH for active-                         Compound (5)               carbon-treatment                         (n = 2) content    ______________________________________    Example 19   5.8         <0.1 wt. %    Example 20   9.2         <0.1 wt. %    ______________________________________

EXAMPLE 21

To 84 g of deionized water was added 19.0 g (0.165 mol) of L-proline andthe mixture was cooled to about 5° C. Under agitation, a 30 wt. %aqueous solution of NaOH was added dropwise slowly at about 0° C. to 3°C. to adjust the pH to 7.3 to 7.9. Under nitrogen gas and with theabove-mentioned pH maintained, 29.2 g (0.162 mol) ofD-α-methyl-β-acetylthiopropionyl chloride was added dropwise over about15 hours with stirring at 0° C. to 3° C. 0 After completion of dropwiseaddition, the reaction was further continued until the consumption of a30 wt. % aqueous solution of NaOH had ceased almost completely. Thisreaction mixture was adjusted to pH 7 by adding a 35 wt. % aqueoussolution of HCl slowly thereto at about 3° C. with constant stirring. Tothis aqueous solution was added 4.2 g of active carbon and the mixturewas stirred at room temperature for about 30 minutes. The carbon wasthen filtered off and washed with about 36 ml of deionized water. Thefiltrate was heated under agitation and acidified to pH about 1.5 with a35 wt. % aqueous solution of HCl at about 70° C. This solution wascooled at a rate of about 0.5° C. /15 min. to let crystals separate outslowly under intense agitation. After this crystallization, the reactionmixture was further cooled to room temperature under gentle agitationand this gentle agitation was continued at room temperature for about 1hour. The crystals were harvested by filtration, rinsed with about 56 mlof cold water, drained well, and dried in vacuo at about 40° C. Theyield of N-(D-α-methyl-β-acetylthiopropionyl)-L-proline was 35.2 g(0.135 mol) or 84 mol % based on D-α-methyl-β-acetylpropionyl chloride.The proportion of compound (5)(n=2) was 0.1 wt. %.

EXAMPLE 22

The same crystals of N-(D-α-methyl-β-acetylthio-propionyl)-L-proline asused in Example 10 which contained 2.0 wt. % of compound (5)(n=2)!, 100grams, was added to a 30 wt. % aqueous solution of NaOH (about 3.2equivalents of NaOH based onN-(D-α-methyl-β-acetylthiopropionyl)-L-proline) over about 25 minutesunder agitation. After completion of addition, the reaction wascontinued for about 10 minutes. The reaction temperature wasconsistently controlled at 0° C. to 5° C. and the reaction pH wasmaintained over 13.2 throughout. Analysis by HPLC revealed that thereaction rate was 100% and that the proportion ofN-(α-methyl-β-(β-methyl-β-hydroxycarbonyl)ethylthiopropionyl)-L-prolinerelative to captopril was 0.5 wt. %.

EXAMPLE 23

The same crystals of N-(D-α-methyl-β-acetylthiopropionyl)-L-proline asobtained in Example 14 which contained 0.3 wt. % of compound (5)(n=2)!,14.0 grams, was added to a mixture of 34 ml of deionized water and 23.0g of 30 wt. % NaOH/H₂ O over 5 hours at a constant internal temperatureof 30° C. under agitation. After completion of addition, the stirringwas further continued at 30° C. for 1 hour. The final pH was 13.4.Analysis of the reaction mixture revealed that there was no residue ofN-(D-α-methyl-β-acetylthiopropionyl)-L-proline and that the yield ofcaptopril was 99 mol %. The proportion of BA-CP relative to captoprilwas less than 0.1 wt. %.

EXAMPLES 24 AND 25 AND REFERENCE EXAMPLE 13

The same crystals of N-(D-α-methyl-β-acetylthiopropionyl)-L-proline asprepared in Example 14 which contained 0.3 wt. % of compound (5)(n=2)!,14.0 grams, was added to a mixture of 34 ml of deionized water and 30wt. % NaOH/H₂ O over 30 minutes at a constant internal temperature ofabout 5° C. under agitation. In the course following the start ofaddition of N-(D-α-methyl-β-acetylthiopropionyl)-L-proline crystals tillcompletion of the reaction, a 30 wt. % aqueous solution of NaOH wasadded so as to maintain the pH at the level indicated in Table 9. Aftercompletion of the reaction, the reaction mixture was analyzed for theyield of captopril and the proportion of BA-CP relative to captopril.The results are shown in Table 9.

                  TABLE 9    ______________________________________                       Yield of BA-CP                pH     captopril                                content    ______________________________________    Reference Example 13                  12.8     99 mol %  0.2 wt. %    Example 24    13.6     99 mol % <0.1 wt. %    Example 25    14.5     99 mol % <0.1 wt. %    ______________________________________

EXAMPLE 26

The Schotten-Baumann reaction was carried out in the same manner asExample 4 except that 12 g of active carbon was fed at the point of timewhen about three-quarters of the necessary amount ofD-α-methyl-β-acetylthiopropionyl chloride had been added. The proportionof by-products relative toN-(D-α-methyl-β-acetylthiopropionyl)-L-proline in the reaction mixturewere as follows.

N-acetyl-L-proline: 1 to 2 wt. %

Captopril 0.2 wt. %

Compound (6) : not detected

Compound (5)(n=2) : not detected

EXAMPLE 27

To 203 g of deionized water were added 38.0 g (0.330 mol) of L-prolineand 74.9 g (0.748 mol) of potassium hydrogencarbonate and the mixturewas cooled to about -3° C. to 0° C. Under nitrogen and with constantagitation, 58.4 g (0.324 mol) of D-α-methyl-β-acetylthiopropionylchloride was added dropwise over 4 hours at -3° C. to 0° C. Aftercompletion of dropwise addition, the reaction was further continuedunder the same conditions for 1 hour. The yield ofN-(D-α-methyl-β-acetylthiopropionyl)-L-proline based onD-α-methyl-β-acetylthiopropionyl chloride in the reaction mixture was 89mol % and the proportion of compound (5)(n=2) relative toN-(D-α-methyl-β-acetylthiopropionyl)-L-proline was 0.1 wt. % During thereaction, the range of pH was 7.4 to 8.8.

EXAMPLE 28

To 110 g of deionized water were added 19.0 g (0.165 mol) of L-prolineand 33.0 g (0.330 mol) of potassium hydrogencarbonate and the mixturewas cooled to about -3° C. to 0° C. Under nitrogen and with constantagitation, 29.2 g (0.162 mol) of D-α-methyl-β-acetylthiopropionylchloride was added dropwise over 1 hour at -3° C. to 0° C. . Aftercompletion of dropwise addition, the reaction was further continuedunder the same conditions for 1 hour. The yield of agitation, a 30 wt. %aqueous solution of NaOH was gradually added dropwise at about 0° C. to3° C. so as to adjust the pH to 9.3. Under nitrogen and with the pHmaintained at 9.4 to 9.7, 31.3 g (0.173 mol) ofD-α-methyl-β-acetylthiopropionyl chloride was added dropwise over about1 hour at 2° C. to 5° C. with stirring at an agitation intensity ofabout 1.5 kW/m³. After completion of dropwise addition, the reaction wasfurther continued under the same conditions for about 2 hours. Undernitrogen, this reaction mixture was adjusted to pH 7 with 35 wt. %HCl/H₂ O at about 1° C. To this solution was added 15.0 g of activecarbon and the mixture was stirred under nitrogen at about 20° C. for 1hour. The carbon was then filtered off and washed with about 100 ml ofdeionized water. Under nitrogen gas, the filtrate was added to3.4N-NaOH/H₂ O about 3.4 equivalents of NaOH based onN-(D-α-methyl-β-acetylthiopropionyl)-L-proline! over about 30 minutes ata constant internal temperature of about 2° C. to 7° C. with stirring.The reaction was further continued under nitrogen for about 2 hours. Thefinal pH was over 13.0. Then, 35 wt. % HCl/H₂ O was added dropwise so asto bring the pH to 7. At an internal temperature of about 20° C. sodiumchloride was added till substantial saturation and the mixture wasfurther stirred for about 1 hour. At an internal temperature of about20° C. to 30° C. 35 wt. % HCl/H₂ O was slowly added dropwise underintense stirring until the pH became 3.4 and this intense stirring wasfurther continued for about 1 hour. To the resulting slurry was added afurther amount of 35 wt. % HCl/H₂ O dropwise over more than 1 hour at aninternal temperature of about 20° C. to 30° C. to bring the pH to 3.0and the intense stirring was continued for 1 hour. Then, at an internaltemperature of about 20° C. to 30° C. 35 wt. % HCl/H₂ O was addeddropwise over about 1 hour to adjust the pH to 1. The intense stirringwas further continued in this condition for 30 minutes and the mixturewas cooled to an internal temperature of 2° C. At this internaltemperature of about N-(D-α-methyl-β-acetylthiopropionyl)-L-prolinebased on D-α-methyl-β-acetylthiopropionyl chloride in the reactionmixture was 81 mol %. Compound (5)(n=2) was not detected. The range ofpH was 7.2 to 8.9 during the reaction.

EXAMPLE 29

To 85 g of deionized water was added 19.0 g (0.165 mol) of L-proline andthe mixture was cooled to about 5° C. Under agitation, a 30 wt. %aqueous solution of NaOH was slowly added dropwise at about 0° C. to 3°C. so as to adjust the pH to 8.5. Then, under nitrogen and with the pHmaintained between 8.3 and 8.7, 29.2 g (0.162 mol) ofD-α-methyl-β-acetylthiopropionyl chloride was added dropwise over about1 hour at 2° C. to 5° C. with stirring at an agitation intensity ofabout 1.5 kW/m³. After completion of dropwise addition, the reaction wasfurther continued under the same conditions for about 2 hours. Undernitrogen, the reaction mixture thus obtained was adjusted to pH 4.5 to5.0 by adding a 35 wt. % aqueous solution of HCl thereto dropwise atabout 1° C. and, then, heated to about 60° C. Under intense agitation,35 wt. % HCl/H₂ O was further added so as to reduce the pH by about 0.2in every 15 minutes until the pH reached 2.5 to let crystals separateout. After gradual cooling to about 10° C. a further amount of 35 wt. %HCl/H₂ O was added so as to adjust the pH to 1.5 and the mixture wasfurther stirred gently for about 1 hour. The crystals that had separatedout were harvested by filtration, drained well, rinsed with about 60 mlof cold water, and drained well again to provide wet crystals ofN-(D-α-methyl-β-acetylthiopropionyl)-L-proline yield 89%; containing 0.2wt. % of compound (5)(n=2) and not more than 0.1 wt. % ofN-acetyl-L-proline!.

EXAMPLE 30

To 101 g of deionized water was added 19.0 g (0.165 mol) of L-prolineand the mixture was cooled to about 5° C. Under 2° C., the intensestirring was continued for 4 hours. The resulting slurry was separatedand washed twice with about 15 ml of cold water. The wet crystals thusobtained were dried in vacuo (1 to 5 mmHg) at a temperature not over 40°C. The yield of captopril was 28.2 g (0.130 mol) or 79 mol % based onL-proline and 75 mol % based on D-α-methyl-β-acetylthiopropionylchloride.

The description and properties of the product captopril were as follows.

White crystals, substantially odorless

m.p. 106° C. (melting-point standard: acetanilide)

α!_(D) ²⁵ =-128° C. (c=1.0, EtOH, 100 mm)

HPLC purity 99.5 wt. %

Titrimetric purity 99.5%

Disulfide content 0.2 wt. %

β-Mercapto-α-methylpropionic acid content <0.1 wt. %

N- α-methyl-β-(β-methyl-β-hydroxycarbonyl)-ethylthiopropionyl!-L-prolinecontent <0.1 wt. %

N-acetyl-L-proline content 0.1 wt. %

Otherwise, no specific impurity was detected on the HPLC.

EXAMPLE 31

To 85 g of deionized water was added 19.0 g (0.165 mol) of L-proline andthe mixture was cooled to about 5° C. Under agitation, a 30 wt. %aqueous solution of NaOH was slowly added dropwise at 0° C. to 3° C. tobring the pH to 9.0. Under nitrogen and with the pH maintained at 8.9 to9.4, 29.2 g (0.162 mol) of D-α-methyl-β-acetylthiopropionyl chloride wasadded dropwise over about 1 hour at 2° C. to 5° C. with stirring at anagitation intensity of about 1.5 kW/m³. After completion of dropwiseaddition, the reaction was further continued under the same conditionsfor about 2 hours. Under nitrogen, this reaction mixture was adjusted topH 7 by adding 35 wt. % HCl/H₂ O dropwise thereto at about 1° C. and,then, heated to about 60° C. Then, under intense stirring, the mixturewas acidified with 35 wt. % HCl/H₂ O to let crystals separate out in anitrogen atmosphere. The 35 wt. % aqueous solution of HCl was added fasttill pH 5 and, then, dropwise at a rate of pH about 0.2/15 min. till pH3 to let crystals separate out slowly. The addition speed was thenincreased gradually until the final pH 1.5 was established. Then, thereaction mixture was gradually cooled to about 10° C. and stirred gentlyfor about 2 hours. The crystals were harvested by filtration, drainedwell, rinsed with about 60 ml of cold water, and drained well to providewet crystals of N-(D-α-methyl-β-acetylthiopropionyl)-L-proline (yield89%, compound (5)(n=2) content 0.2 wt. %). Under nitrogen, the wetcrystals were added to 3.4N-NaOH/H₂ O (about 3.3 equivalents of NaOHbased on N-(D-α-methyl-β-acetylthiopropionyl)-L-proline) over about 30minutes at a constant internal temperature of about 2° C. to 7° C. withagitation. The reaction was further continued under nitrogen for about 2hours and at the stage of pH about 14, 35 wt. % HCl/H₂ O was addeddropwise so as to adjust the reaction mixture to pH 7. Then, at aninternal temperature of about 3° C. to 25° C., sodium chloride was addeduntil substantial saturation and the mixture was stirred for about 1hour. At an internal temperature of 40° C. 35 wt. % HCl/H₂ O was slowlyadded dropwise to bring the pH to 3.4 under intense agitation and theintense agitation was continued for about 1 hour. To the resultingslurry, at an internal temperature of 40° C. was added a further amountof 35 wt. % HCl/H₂ O dropwise over about 1 hour to lower the pH to 3.0and the mixture was stirred intensely for 1 hour. Then, at an internaltemperature of 40° C. a further amount of 35 wt. % HCl/H₂ O was addeddropwise over 20 minutes to bring the pH to 1.8. The intense stirringwas continued for 30 minutes and with the pH maintained at 1.8 bydropwise addition of 35 wt. % HCl/H₂ O, the mixture was cooled to aninternal temperature of 4° C. The reaction mixture was further cooled toabout 1° C. and maintained under intense agitation at that temperaturefor 30 minutes. The resulting slurry was filtered and washed twice withabout 15 ml portions of cold water. The wet crystals thus obtained weredried in vacuo (1 to 5 mmHg) at a temperature not exceeding 40° C. Theyield of captopril was 27.5 g (0.127 mol). The yield of captopril basedon L-proline was 77 mol % and that based onD-α-methyl-β-acetylthiopropionyl chloride was 78 mol %.

The description and properties of the above product captopril were asfollows.

White crystals, substantially odorless

m.p. 107° C. to 108° C. (melting-point standard: acetanilide)

α!_(D) ²⁵ =-128° C. (c=1.0 EtOH, 100 mm)

HPLC purity 99.7 wt. %

Titrimetric purity 99.7%

Disulfide content 0.1 wt. %

β-Mercapto-α-methylpropionic acid content <0.1%

N- α-methyl-β-(β-methyl-β-hydroxycarbonyl)-ethylthiopropionyl!-L-prolinecontent <0.1 wt. %

N-acetyl-L-proline content 0.1 wt. %

No other impurity peak was detected on the HPLC.

EXAMPLE 32

To 85 g of deionized water was added 19.0 g (0.165 mol) of L-proline andthe mixture was cooled to about 5° C. Under agitation, a 30 wt. %aqueous solution of NaOH was slowly added dropwise thereto at about 0°C. to 3° C. to bring the pH to 9.5. Under nitrogen and with the pHmaintained at 9.3 to 9.7, 29.2 g (0.162 mol) ofD-α-methyl-β-acetylthiopropionyl chloride was added dropwise over about1 hour at 2° C. to 5° C. with stirring at an agitation intensity ofabout 1.5 kW/m³. After completion of dropwise addition, the ripeningreaction was continued under the same conditions for about 1 hour. Thisreaction mixture was adjusted to pH 7 by dropwise addition of 35 wt. %HCl/H₂ O at about 1° C. under nitrogen gas.

To this solution was added 12.0 g of active carbon and the mixture wasstirred at about 20° C. under nitrogen for 2 hours.

The carbon was then filtered off and washed with 55 ml of deionizedwater. This solution was adjusted to pH 7 and heated to about 50° C.under nitrogen gas. Under intense agitation, the mixture was acidifiedwith 35 wt. % HCl/H₂ O to let crystals separate out under nitrogen gas.The 35 wt. % aqueous solution of HCl was added fast till pH 5 anddropwise at a rate of pH about 0.2/15 min. till pH 3 to let crystalsseparate out slowly. The addition speed was then increased to adjust thepH to 1.5. The reaction mixture was gradually cooled to about 10° C. andstirred gently for about 2 hours. The crystals that had separated outwere harvested by filtration, drained well, rinsed with about 60 ml ofcold water, and drained well to provide wet crystals ofN-(D-α-methyl-β-acetylthiopropionyl)-L-proline (yield˜90%; compound(5)(n=2) content <0.1 wt. %). The wet crystals thus obtained were addedto 3.4N-NaOH/H₂ O (about 3.2 equivalents of NaOH based onN-(D-α-methyl-β-acetylthiopropionyl)-L-proline) over 30 minutes in anitrogen gas at an internal temperature of about 2° C. to 7° C. underconstant agitation. The reaction was further continued under nitrogengas for about 2 hours and at the stage of pH 13.5, the reaction mixturewas adjusted to pH 7 by dropwise addition of 35 wt. % HCl/H₂ O. Then, atan internal temperature of about 3° C. to 25° C. about 30 g of sodiumchloride was added and the mixture was stirred for about 1 hour. At aninternal temperature of 30° C., 35 wt. % HCl/H₂ O was slowly addeddropwise to bring the pH to 3.4 under intense agitation and the intensestirring was continued for about 1 hour. To the resulting slurry, at aninternal temperature of 30° C., was added a further amount of 35 wt. %HCl/H₂ O dropwise over not less than 1 hour to lower the pH to 3.0. Theintense stirring was then continued for 1 hour. Then, at an internaltemperature of 30° C., 35 wt. % HCl/H₂ O was added dropwise over 20minutes to bring the pH to 1.8. The mixture was further stirred for 30minutes and with the pH maintained with 35 wt. % HCl/H₂ O, the reactionmixture was cooled to an internal temperature of 4° C. The temperaturewas further lowered to about 1° C. and the mixture was stirred gentlyfor 30 minutes. The resulting slurry was filtered and washed twice withabout 15 ml portions of cold water. The wet crystals were then dried invacuo (1 to 5 mmHg) at about 40° C. The yield of captopril was 27.3 g(0.126 mol). The yield based on L-proline was 76 mol % and the yieldbased on D-α-methyl-β-acetylthiopropionyl chloride was 78 mol %.

The description and properties of the product captopril were as follows.

White crystals, substantially odorless

m.p. 107° C. to 108° C. (melting-point standard: acetanilide) α!_(D) ²⁵=-129° C. (c=1.0, EtOH, 100 mm)

HPLC purity 99.9 wt. %

Titrimetric purity 99.9%

Disulfide content 0.1 wt. %

ββ-Mercapto-α-methylpropionic acid content <0.1%

N- α-methyl-β-(β-methyl-β-hydroxycarbonyl)-ethylthiopropionyl!-L-prolinecontent <0.1 wt. %

N-acetyl-L-proline content <0.1 wt. %

Otherwise, no specific impurity peak was detected on the HPLC.

REFERENCE EXAMPLE 14

Using the various reaction mixtures the proportion ofN-(α-methyl-β-(β-methyl-β-hydroxycarbonyl)ethylthiopropionyl)-L-prolinerelative to captopril: 0.1 to 3.0 wt. %! obtained by the deacylationreaction, which was carried out in the same manner as described in theforegoing examples and reference examples, of several grades ofN-(D-α-methyl-β-acetylthiopropionyl)-L-proline varying in compound (5)and compound (6) contents, captopril was crystallized out in the samemanner as described in Examples 27 to 29 and the harvested crystals wererinsed and dried to provide captopril crystals (yields: about 85 mol %).The elimination rate ofN-(α-methyl-β-(α-methyl-β-hydroxycarbonyl)ethylthiopropionyl)-L-prolinein the product captopril was not higher than about 50% and theelimination rate tended to be fairly low when theN-(α-methyl-β-β-methyl-β-hydroxycarbonyl)ethylthiopropionyl)-L-prolinecontent was low. It was, therefore, found very difficult to removeN-(α-methyl-β-(β-methyl-β-hydroxycarbonyl)-ethylthiopropionyl)-L-prolinefrom captopril with efficiency while upholding the yield ofwater-soluble captopril.

INDUSTRIAL APPLICABILITY

In accordance with the present invention, there is provided a highlyexpedient and efficient process for producing a high-melting,high-quality grade of N-(D-α-methyl-β-mercaptopropionyl)-L-proline (4)(captopril) with minimal impurities, particularly with a very lowcontent of N-α-methyl-β-(β-methyl-β-hydroxycarbonyl)-ethylthiopropionyl)-L-proline(7) and other impurities difficult to remove, in high yields and at lowcost. There can also be provided a highly expedient and efficientprocess for producing a high qualityN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) orN-(DL-α-methyl-β-acylthiopropionyl)-L-proline, which is an intermediatefor the synthesis of N-(D-α-methyl-β-mercaptopropionyl)-L-proline (4)(captopril), with a minimal content of precursors of N-α-methyl-β-(β-methyl-β-hydroxycarbonyl)ethylthiopropionyl!-L-proline (7)and other impurities, in high yields and at low cost.

We claim:
 1. A process for producing high purityN-(D-α-methyl-β-mercaptopropionyl)-L-proline of the formula (4)##STR12## by subjecting a D-α-methyl-β-acylthiopropionic acid halide ofthe general formula (1) ##STR13## (wherein R¹ represents an acyl groupand X represents a halogen), and L-proline of the formula (2) ##STR14##to Schotten-Baumann reaction in a basic aqueous medium in the presenceof a deacidifying condensing agent to give the correspondingN-(D-α-methyl-β-acylthiopropionyl)-L-proline of the general formula (3)##STR15## (wherein R¹ is as defined above), followed by deacylation,which comprises carrying out the deacylation of theN-(D-α-methyl-β-acylthiopropionyl)-L-proline after removal of thoseimpurities concurrently formed with the above-mentioned objectivesubstance N-(D-α-methyl-β-mercaptopropionyl)-L-proline, in theirprecursor stage, from the aqueous medium solution after commencement butbefore completion of said Schotten-Baumann reaction or after completionthereof by treating said aqueous medium solution with active carbon at apH not higher than 12 wherein the aqueous medium is water essentiallyfree of any organic solvent.
 2. The process according to claim 1,wherein, in the Schotten-Baumann reaction, saidD-α-methyl-β-acylthiopropionic acid halide (1) is used in the form ofDL-α-methyl-β-acylthiopropionic acid halide to give theN-(DL-α-methyl-β-acylthiopropionyl)-L-proline, which is then subjectedto optical resolution to give theN-(D-α-methyl-β-acylthioproplonyl)-L-proline (3).
 3. The processaccording to claim 1, wherein the Schotten-Baumann reaction is carriedout at a temperature of 10° C. or below and a pH of 7.3 to 10.2 withstirring at an intensity of 0.1 kW/m³ or more.
 4. The process accordingto claim 1, wherein the deacylation is carried out at a pH not less than13 in an aqueous medium containing at least one alkali selected from thegroup consisting of sodium hydroxide, potassium hydroxide and lithiumhydroxide.
 5. The process according to claim 1, wherein the acyl groupis acetyl.
 6. A process for producing high purityN-(D-α-methyl-β-mercaptopropionyl)-L-proline of the formula (4)##STR16## by subjecting a D-α-methyl-β-acylthiopropionic acid halide ofthe general formula (1) ##STR17## (wherein R¹ represents an acyl groupand X represents a halogen), and L-proline of the formula (2) ##STR18##to Schotten-Baumann reaction in a basic aqueous medium in the presenceof a deacidifying condensing agent to give the correspondingN-(D-α-methyl-β-acylthiopropionyl)-L-proline of the general formula (3)##STR19## (wherein R¹ is as defined above), followed by deacylation,which comprises collecting theN-(D-α-methyl-β-acylthiopropionyl)-L-proline by causing the same toperform crystallization at 35° C. to 100° C. under acidic conditionsfrom the aqueous medium solution after completion of theSchotten-Baumann reaction, thus removing those impurities concurrentlyformed with the above-mentioned objective substanceN-(D-α-methyl-β-mercaptopropionyl)-L-proline, in their precursor stage,and subjecting the thus-collectedN-(D-α-methyl-β-acylthiopropionyl)-L-proline, either as such or afterstorage, to the deacylation wherein the aqueous medium is wateressentially free of any organic solvent.
 7. The process according toclaim 6, wherein the crystallization of theN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) is carried out afteractive-carbon-treatment of the aqueous medium solution aftercommencement but before completion of the Schotten-Baumann reaction orafter completion thereof.
 8. The process according to claim 6, wherein,in the Schotten-Baumann reaction, the D-α-methyl-β-acylthiopropionicacid halide (1) is used in the form of DL-α-methyl-β-acylthiopropionicacid halide to give the N-(DL-α-methyl-β-acylthiopropionyl)-L-proline,followed by optical resolution to give theN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3).
 9. The processaccording to claim 6, wherein the crystallization is carried out at 40°C. to 70° C.
 10. The process according to claim 6, wherein theSchotten-Baumann reaction is carried out at a temperature of 10° C. orbelow and a pH of 7.3 to 10.2 with stirring at an intensity of 0.1 kW/m³or more.
 11. The process according to claim 6, wherein the deacylationis carried out at a pH not less than 13 in an aqueous medium containingat least one alkali selected from the group consisting of sodiumhydroxide, potassium hydroxide and lithium hydroxide.
 12. The processaccording to claim 6, wherein the acyl group is acetyl.
 13. A processfor producing a high purity N-(D-α-methyl-β-acylthiopropionyl)-L-prolinewhich comprises treating with active carbon at a pH of 12 or below anaqueous medium solution of theN-(D-α-methyl-β-acylthiopropionyl)-L-proline of the general formula (3)##STR20## (wherein R¹ is an acyl group), which solution contains atleast one impurity selected from the group consisting of compounds ofthe general formula (5) ##STR21## (wherein n is an integer of 2 to 4 andR¹ is as defined above), and the compound of the formula (6) ##STR22##to thereby remove the compound or compounds, coexisting as impurities,of the general formula (5) and the formula (6) wherein the aqueousmedium is water essentially free of any organic solvent.
 14. The processaccording to claim 13, wherein saidN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) is used in the form ofN-(DL-α-methyl-β-acylthiopropionyl)-L-proline.
 15. The process accordingto claim 13, wherein the acyl group is acetyl.
 16. A process forproducing a high purity N-(D-α-methyl-β-acylthiopropionyl)-L-prolinewhich comprises causing an N-(D-α-methyl-β-acylthiopropionyl)-L-prolineof the general formula (3) ##STR23## (wherein R¹ is an acyl group), toperform crystallization at 35° C. to 100° C. under acidic conditionsfrom an aqueous medium solution of the compound of general formula (3)containing at least one impurity selected from the group consisting ofcompounds of the general formula (5) ##STR24## (wherein n is an integerof 2 to 4 and R¹ is as defined above), and the compound of the formula(6) ##STR25## to thereby remove the compound or compounds, coexisting asimpurities, of the general formula (5) and the formula (6) wherein theaqueous medium is water essentially free of any organic solvent.
 17. Theprocess according to claim 16, wherein saidN-(D-α-methyl-β-acylthiopropionyl)-L-proline (3) is used in the form ofN-(DL-α-methyl-β-acylthiopropionyl)-L-proline.
 18. The process accordingto claim 16 wherein the crystallization is carried out at 40° C. to 70°C.
 19. The process according to claim 16, wherein the acyl group isacetyl.